Is DCLRE1C p.Ser32Phe (c.95C>T) pathogenic?

DCLRE1C p.Ser32Phe (c.95C>T) is classified Likely pathogenic in DCLRE1C (ClinVar, Expert panel, 6 submitters; last evaluated 2024-01-23). AlphaMissense: likely pathogenic (0.9991); Very rare (popmax 0.00017%, nfe); Associated with severe combined immunodeficiency due to DCLRE1C deficiency.

How common is DCLRE1C p.Ser32Phe (c.95C>T) in the general population?

DCLRE1C p.Ser32Phe (c.95C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about DCLRE1C p.Ser32Phe (c.95C>T)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

DCLRE1C p.Ser32Phe

Q: What condition is associated with DCLRE1C p.Ser32Phe (c.95C>T)?

DCLRE1C p.Ser32Phe (c.95C>T) is associated with severe combined immunodeficiency due to DCLRE1C deficiency, Aicardi-Goutieres syndrome 1, Omenn syndrome (ClinVar).

Q: How is Severe combined immunodeficiency due to DCLRE1C deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.95C>T · rs969498121 · VCV1438811

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

severe combined immunodeficiency due to DCLRE1C deficiency

ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP

Likely Pathogenic for severe combined immunodeficiency due to DCLRE1C deficiency. Applied ACMG criteria (verbatim):

PM2_Supporting PS3_Moderate PP4_Supporting PM3_Moderate

Curation rationale (ClinGen, verbatim)

The c.95C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Phenylalanine at amino acid 32 (p.Ser32Phe). The filtering allele frequency (the upper threshold of the 95% CI of 2/1111892 alleles) of the c.95C>T variant in DCLRE1C is 0.0000003 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). At least one patient in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + T-B-NK+ lymphocyte subset profile 0.5 pts, total 1 pt; Which is highly specific for SCID. PP4_Supporting (PMIDs: 18223550 and 25917813 - same patient). The proband is compound heterozygous, in trans, for del Ex1-3 (at least LP according to our SCID VCEP specifications;) 1 point, PM3_Moderate. (PMID: 25917813). Activity levels in % of WT activity = Recombination: Mean (SD): 5.14 (0.34) and DNA repair (36h after IR): Mean (SD): 20.95 (6.17). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level(PMID: 25917813). In summary, this variant is classified as a Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4_Supporting, PM3_Moderate, and PS3_Moderate.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic ✓ concordant with ClinVar · top 1% in DCLRE1C
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -16.00	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 46 kb · p 0.034 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,932 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,668 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
European (non-Finnish)grpmax	0.00017%	589,967

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DCLRE1C
Protein: p.Ser32Phe
Coding: c.95C>T
MANE Select: NM_001033855
dbSNP: rs969498121
Type: single nucleotide variant
Location: chr10:14953916 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.10 · 14 PDB
Residue 32: a β-strand

Full DCLRE1C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

severe combined immunodeficiency due to DCLRE1C deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Aicardi-Goutieres syndrome 1 Omenn syndrome severe combined immunodeficiency Ehlers-Danlos syndrome, kyphoscoliotic type 1

For Severe combined immunodeficiency due to DCLRE1C deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DCLRE1C p.Ser32Cys Likely pathogenic ★★★ same residue
DCLRE1C p.Ser32= Likely benign ★ same residue
DCLRE1C c.109+1G>T Pathogenic ★★★ same condition
DCLRE1C c.161+2T>G Pathogenic ★★★ same condition
DCLRE1C p.Ala28Pro Likely pathogenic ★★★ same condition
DCLRE1C p.Arg191Ter Pathogenic ★★★ same condition
DCLRE1C p.Arg383Ter Pathogenic ★★★ same condition
DCLRE1C p.Arg81Ter Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dclre1c-p-ser32phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown